Rabies is a viral zoonosis, and affects mainly wild animals and companion animals as well as mammals including humans, and thus causes acute brain diseases. Rabies is a fatal disease that entails the risk of death through a single infection, and is known to be the disease having the highest mortality rate with AIDS. Such rabies is spread all over the world, with more than 10 million people being treated after infection every year, with 40,000 to 70,000 deaths each year.
Rabies is transmitted through saliva and blood, and is usually caused by being bitten by rabies-infected dogs or cats. It may also be carried by most mammals, including skunks, bats, and the like.
The rabies virus exhibits actual onset symptoms after reaching the cranial nerves through the terminal nerve tissue of the body. The human brain originally contains a blood brain barrier that blocks the invasion of external substances, so that viruses cannot penetrate. However, the rabies virus infects the central nervous system of the brain by passing through the blood brain barrier via RVG protein (rabies virus glycoprotein).
In addition to symptoms similar to colds at the beginning of rabies, itching or fever is felt in the bite area. As rabies progresses, there may occur neurological abnormalities, such as anxiety, hydrophobia (swallowing of liquids such as water causes spasm of the muscles and severe pain to thus incur fear of water), fear of wind (wind makes the sensory organs more sensitive), excitement, paralysis, mental disorder, etc. It also causes hypersensitivity to sunlight. After 2 to 7 days of observation of these symptoms, the nerves and muscles of the entire body are paralyzed, inducing a coma, resulting in respiratory failure leading to death.
Treatment after exposure to rabies includes an injury by biting (post-exposure prophylaxis). An injury by biting includes administration of the antibody for passive immunization and immediate topical wound protection (anti-rabies immunoglobulin: hereinafter, referred to as “anti-rabies antibody”), and administration of the vaccine for active immunization. The currently developed anti-rabies antibody includes human-derived rabies immunoglobulin (hereinafter, referred to as “HRIG”) and equine-derived rabies immunoglobulin (hereinafter, referred to as “ERIG”). HRIG is not efficiently supplied, is expensive, and is a polyclonal antibody, and thus has low efficacy per unit weight. Furthermore, HRIG is derived from the human blood and has a high risk of potential infection of human-derived disease such as HIV. On the other hand, ERIG is inexpensive but exhibits low therapeutic efficiency compared to HRIG, and is thus administered in a much higher dose to patients. However, ERIG is an antibody derived from horses, different from humans, and may thus cause anaphylaxis. Accordingly, in order to overcome the inefficient supply and problems with the polyclonal antibody, the use of a monoclonal antibody that is able to neutralize the rabies virus has been proposed. In the 1980s, a rabies-virus-neutralizing mouse monoclonal antibody was developed (Schumacher C L et al., J. Clin. Invest. Vol. 84, p. 971-975, 1989), but the direct administration thereof to human patients is limited owing to defects such as a short half-life in the human body, the absence of an antibody-mediated immune response, induction of HAMA (human anti-mouse antibody), and the like.
Moreover, the WHO has presented several recommendations to replace existing HRIG or ERIG (WHO Consultation on a Rabies Monoclonal Antibody Cocktail for Rabies Post-Exposure Treatment. WHO, Geneva, 23-24 May 2002). Among these, it has been proposed that in order for the monoclonal antibody to serve as a therapeutic agent for rabies, two or three antibodies should be cocktailed and bound to different sites of the rabies virus surface glycoprotein.
Therefore, for effective rabies treatment, there is an urgent need to develop a human monoclonal antibody and an antibody cocktail against any rabies virus, which are not derived from the blood to thus have high safety against potential infection, enable mass production through incubation, and are composed exclusively of antibodies having efficacy to thus ensure uniform quality and exhibit high efficiency per unit dose.